We have demonstrated that the transferrin (Tf) receptor is a highly regulated molecule. It enters the cell through the classic pathway of endocytosis but only when activated by the appropriate signals. These can be given by either ligand or anti-receptor antibody or by activation or protein kinase C using phorbol esters. The latter result in a dramatic increase in receptor phosphorylation. Once inside the cell, ligand-driven receptors recycle to the plasma membrane. In contrast, antibody-driven receptor moves to the lysosomes where it is degraded. Using normal peripheral blood human T cells, we have demonstrated that only an agonistic ligand such as IL-2 will stimulate the internalization of the T cell growth factor receptor. Anti-receptor antibodies with antigonistic activity are not internalized. We have shown that the regulation of the human Tf receptor by iron occurs via alterations in the level of the mRNA for the receptor. The cells sense a very labile pool of iron and even the process of down regulating receptors results in a rapid enhancement of receptor biosynthesis. This may explain why all growing cells need to be continuously exposed to Tf. Consistent with the rapid sensing of iron by the genome, we find that a small percentage of iron released in the cell by Tf is rapidly delivered to the nucleus.